Crosstalk between Inflammation and the BBB in Stroke

Abstract

The blood-brain barrier (BBB), which is located at the interface between the central nervous system (CNS) and the circulatory system, is instrumental in establishing and maintaining the microenvironmental homeostasis of the CNS. BBB disruption following stroke promotes inflammation by enabling leukocytes, T cells and other immune cells to migrate via both the paracellular and transcellular routes across the BBB and to infiltrate the CNS parenchyma. Leukocytes promote the removal of necrotic tissues and neuronal recovery, but they also aggravate BBB injury and exacerbate stroke outcomes, especially after late reperfusion. Moreover, the swelling of astrocyte endfeet is thought to contribute to the 'no-reflow' phenomenon observed after cerebral ischemia, that is, blood flow cannot return to capillaries after recanalization of large blood vessels. Pericyte recruitment and subsequent coverage of endothelial cells (ECs) alleviate BBB disruption, which causes the transmigration of inflammatory cells across the BBB to be a dynamic process. Furthermore, interneurons and perivascular microglia also make contacts with ECs, astrocytes and pericytes to establish the neurovascular unit. BBB-derived factors after cerebral ischemia triggered microglial activation. During the later stage of injury, microglia remain associated with brain ECs and contribute to repair mechanisms, including postinjury angiogenesis, by acquiring a protective phenotype, which possibly occurs through the release of microglia-derived soluble factors. Taken together, we reviewed dynamic and bidirectional crosstalk between inflammation and the BBB during stroke and revealed targeted interventions based on the crosstalk between inflammation and the BBB, which will provide novel insights for developing new therapeutic strategies.

Keywords: Stroke; adaptive immunity; blood-brain barrier; inflammation; innate immunity; treatment.

Fig. (1)

BBB disruption promotes inflammation by enabling immune cells. Microglia/macrophages are recruited into the brain tissue within an hour, reach a peak in 24-96h and then gradually decrease to baseline level until 28 days post-stroke; Neutrophils are trapped within the confines of the neurovascular unit and the leptomeningeal spaces during the early phase of reperfusion, however, neutrophils can pass through the junctions of the barrier and being detected after 48h post-stroke; Mast cells increase significantly in the brain tissues in 24h after stroke; T cells are identified in the postischemic brain as early as 24 h and are at peak 72-96h after reperfusion; the presence of T cells persists as late as 7 weeks post-stroke. (A higher resolution / colour version of this figure is available in the electronic copy of the article).